title: A new face of Borjeson-Forssman-Lehmann syndrome? De novo mutations in PHF6 in seven females with a distinct phenotype.
abstract: BACKGROUND
  Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked recessive intellectual disability (ID) disorder caused by mutations in the PHF6 gene and characterised by variable cognitive impairment, a distinct facial gestalt, obesity, and hypogonadism. Female carriers are usually not affected or only mildly affected, and so far only two females with de novo mutations or deletions in PHF6 have been reported.
  
  
  RESULTS
  We performed PHF6 mutational analysis and screening for intragenic deletions and duplications by quantitative real-time PCR and multiplex ligation dependent probe amplification (MLPA) in female patients with variable ID and a distinct appearance of sparse hair, remarkable facial features, hypoplastic nails, and teeth anomalies. We detected two truncating mutations and two duplications of exons 4 and 5. Furthermore, two female patients with PHF6 deletions and a similar phenotype were identified by routine molecular karyotyping. Recently, two patients with a clinical diagnosis of Coffin-Siris syndrome in early infancy had been found to harbour mutations in PHF6, and their phenotype in advanced ages is now described. Further studies revealed skewed X-inactivation in blood lymphocytes, while it was normal in fibroblasts, thus indicating functional mosaicism.
  
  
  CONCLUSIONS
  Our findings indicate that de novo defects in PHF6 in females result in a recognisable phenotype which might have been under-recognised so far and which comprises variable ID, a characteristic facial gestalt, hypoplastic nails, brachydactyly, clinodactyly mainly of fingers IV and V, dental anomalies, and linear skin hyperpigmentation. It shows overlap with BFLS but also additional distinct features, thus adding a new facet to this disorder.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kraus
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Juliane
authors.initials: J
authors.lastname: Hoyer
authors.forename: Walter
authors.initials: W
authors.lastname: Just
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Michael
authors.initials: M
authors.lastname: Zeschnigk
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D005145:Face / Q000002:abnormalities* / Q000473:pathology; D005260:Female; D005385:Fingers / Q000002:abnormalities* / Q000473:pathology; D005528:Foot / Q000473:pathology; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006225:Hand / Q000473:pathology; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000473:pathology; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D012097:Repressor Proteins; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C502542:PHF6 protein, human; D012097:Repressor Proteins
keywords: Clinical genetics